Our goal is to design, fabricate, and validate a novel class of nanofiber-based conduits for the surgical repair of transected peripheral nerves by restoring their continuity and functions. We will take a bioengineering approach to the repair of large defects in thick nerves. Based on knowledge of the anatomy of a peripheral nerve, as well as the biochemistry and cell biology involved in its injury and repair, we will design and fabricat multi-tubular nerve guidance conduits (mNGCs) with a honeycomb structure from a biodegradable polymer by electrospinning. The mNGC will be constructed by inserting a hexagonal array of seven small, single-tubular conduits into a large conduit. The wall of both small and large conduits has a tri-layer structure. A non-woven sheet of random nanofibers will be used as the outer layer to circumvent any possible tearing during surgery, together with an inner layer of uniaxially aligned nanofibers to provide longitudinal guidance for axonal extension. A phase-change material (PCM) sensitive to temperature change will be applied as a thin, porous layer to glue together these two layers of nanofibers. The PCM will be per-loaded with bioactive molecules for pulse release to digest the inhibitory chondroitin sulfate proteoglycan and promote neurite extension. The inner surface of each small conduit will also be seeded with Schwann cells derived from autologous bone mesenchymal stem cells (BMSCs) to support neurite outgrowth. We will evaluate the conduits using clinically relevant animal models capable of recreating the repair features in humans. The scope of this research includes: i) fabrication of the conduits using electrospun nanofibers; ii) in vitro evaluation of the differentiation of BMSCs on various types of nanofiber scaffolds under pulse release of bioactive molecules; iii) evaluation of the efficacy of single-tubular NGCs for sciatic nerve repair in a rat model; and iv) evaluation of the efficacy of multi-tubular NGCs for median nerve repair in an ovine model.